: Diabetic patients have a two-fold higher mortality rate following myocardial infarction than their non-diabetic counterparts. Despite this, the effect of diabetes on ischemic injury is controversial. In some studies, ischemia reperfusion injury is actually reduced in diabetic models. One likely source of this variability is in the levels of cardioprotective and cardiotoxic factors in the diabetic animal. A major goal of the proposed research is to identify some of the regulatory factors found in the diabetic heart. Preliminary data suggest that one of the important factors is hyperglycemia. The proposal introduces the hypothesis that glucose enhances the production of diacylglycerol, leading to activation of protein kinase C, followed by up regulation of the cardioprotective factor, Bcl-2. PKC and Bcl-2 levels will be monitored by Western blot analysis. In addition, the role of catecholamines and angiotensin-2 as factors augmenting ischemic damage and reversing glucose-induced up regulation of Bcl-2 will be examined. The extent of apoptosis, necrosis, mitochondrial membrane potential changes and caspase activation will be examined in the presence of elevated glucose and following treatment with neurohumoral factors prior to a hypoxic stimulus. Cell culture studies will be complimented by studies using an isolated heart model to test the hypothesis that hypertensive diabetic hearts will be more susceptible to an ischemic insole because of elevated levels of angiotensin.